Sorafenib Combined With Cisplatin In The Treatment Of Triple-negative Breast Cancer

Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancer diagnoses. Although triple-negative breast cancer accounts for a relatively small minority of breast cancer cases, it is responsible for a disproportionate number of breast cancer deaths. Meanwhile, this disease often occurs in young women. Multiple data sets have consistently identified poorer clinical outcomes for women with TNBC. Until recently, the subset of breast cancer lacking the expressions of estrogen receptor, progesterone receptor and human epithelial growth factor receptor 2 had no standard therapeutic approach. This study is to investigate the inhibitory proliferation effect of Sorafenib combined with cisplatin (DDP) on TNBC cells and to identify the possible molecular mechanisms by detecting the molecules associated with MAPK signaling pathway, cell cycle and apoptosis.The results of MTT showed that Sorafenib or DDP alone inhibited TNBC cell lines MDA-MB-231, MDA-MB-468, CAL-51 and non-TNBC cell line MCF-7 proliferation dose-dependently in vitro. Compared with non-TNBC cell line MCF-7, TNBC cell lines MDA-MB-468 and CAL-51 were more sensitive to DDP. Based on the median-effect principle, Sorafenib combined with DDP showed a synergistic inhititory effect on the four cell lines proliferation. The potential molecular machenism of Sorafenib with DDP on synergistic inhititory effect was closely related to the blockage or activation of MAPK signling pathways. Western blot analysis indicated p-ERK and P38 protein expression levels decreased, but p-JNK and p-P38 protein expression levels elevated in four cell lines with different degrees. Sorafenib combined with DDP blocked cell cycle progress by Flow Cytometry. Sorafenib with DDP arrested cells in G0/G1 phase and inhibited cell proliferation. Western blot analysis also indicated that decreased expression of CyclinA, CylinB1, CylinD1 and CylinE in the four cell lines would be the reason of cell cycle blockage. Sorafenib with DDP induced cell apoptosis possiblely by inhibiting the expression of Bcl-2 protein.This study suggested that Sorafenib combined with DDP had a synergistic inhibitory effect on TNBC cells proliferation. The mechanisms of synergistic effect were closely related to the regulation on MAPK signaling pathway, blockage of cell cycle progress and the enhancement of apoptosis.Therefore, the findings in this report provide insights into coadministration of Sorafenib and DPP as a regimen in clinical practice in treating TNBC patients.